A novel class of allosteric ligands modulating TRPA1: discovery of a switch in agonist‐antagonist function (1061.7)

Autor: Yingmin Zhu, Yungang Lu, Michael Zhu, Jeffery M. Herz, Edward Kesicki, William J Thomsen
Rok vydání: 2014
Předmět:
Zdroj: The FASEB Journal. 28
ISSN: 1530-6860
0892-6638
Popis: TRPA1 functions as a ligand-gated cation channel in sensory neurons and is an important drug discovery target for identification of novel analgesics. We report identification of a novel structural class of ligands reversibly modulating TRPA1 channel function. Using intracellular calcium measurement and whole cell patch clamp recording of HEK293 cells expressing human TRPA1, we characterized the structure-activity relationships among a group of amino-triarylmethane analogs. A minimal structural change switched a full agonist to antagonist and small changes in side chain substituents in the same ring greatly altered affinity among antagonists. The agonists, ALGX-2014 and ALGX-2015, only elicited TRPA1 currents when applied extracellularly. Their stimulatory effect was blocked by TRPA1 antagonists and unaffected by substituting the three cysteine residues of TRPA1 critical for covalent stimulation by electrophilic agonists, such as AITC and PGJ2, with alanines, suggesting channel activation occurs in a nonco...
Databáze: OpenAIRE
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